The catecholamines such as adrenalin and noradrenalin, the synthetic agonists of these catecholamines which mimic their biological function and the antagonists which block these functions exert their effects by binding to specific recognition sites (adrenergic receptors) situated on cell membranes.
Two main classes of adrenergic receptors have been defined, the .alpha. adrenergic receptors and the .beta. adrenergic receptors.
Within the set of these two classes, four sub-types of these receptors for catecholamines are distinguished (.alpha.1, .alpha.2, .beta.1 and .beta.2-AR). Their genes have recently been isolated and identified (5-8). The analysis of these genes has made it possible to recognize that they belong to a family of integral membrane receptors exhibiting certain homologies (9-10), in particular at the level of the 7 transmembrane regions. These latter are coupled to regulatory proteins, called G proteins, capable of binding molecules of guanosine triphosphate (GTP).
More precisely, the G proteins are proteins having the capacity to intervene structurally and functionally between receptors and enzymes catalysing the production of intracellular mediators (such as adenylate cyclase, guanylate cyclase, the phospholipases, the kinases) or between receptors and ion channels, the controlled opening of which brings about a flux of ions (such as calcium, potassium, sodium, hydrogen ions) into the cell.
These proteins have transduction and coupling functions.
The above-mentioned family of receptors is designated as the "R.sub.7 G family" (10). It comprises, in particular, acetylcholine muscarinic receptors, serotonin receptors, receptors for neuropeptides, substance K and angiotensin II and the visual receptors for the family of the opsins (9-10).
Up until very recently, the definition of the sub-types of receptors was based mainly on the analysis of the physiological properties and binding of different ligands in heterogenous systems. In the R.sub.7 G family, several genes coding for sub-types of receptors defined by their pharmacological properties have been cloned and characterized. Probes obtained from these genes have made it possible to identify additional receptor sub-types (11-12).
The precise nature of the .beta.-adrenergic receptor, which is capable of modulating physiological functions such as thermogenesis in adipose cells as well as intestinal relaxation has remained obscure. In connection with this latter property, it has been found that isoproterenol still inhibits the contractions of the guinea pig ileum induced by the cholinergic pathway (3), in spite of the total blockage of the known adrenergic receptors of the .alpha. and .beta. types with pentholamine and propanolol.
By undertaking a detailed study of the physiological effects of the agonists and of the inhibition by the antagonists of the polypeptides having a .beta.-adrenergic receptor activity (1-3), the hypothesis has been put forward of the existence of a novel sub-type of .beta.-adrenergic receptor.
This hypothesis has been challenged by a conflicting hypothesis, resulting from the analysis of the .beta.-receptor content of an adipose tissue by means of binding studies. This analysis has led to the conclusion--which constitutes the most recent state of the art--that the lipolytic .beta.-adrenergic receptors are uniquely of the .beta.1 sub-type (13).
Moreover, among the compounds used in the modern pharmacopeia, a dominant position is occupied by the .beta.-adrenergic agonists or antagonists (.beta.1 or .beta.2-AR). In spite of their remarkable efficacy, the available medicines can produce side effects, due potentially to the interaction with other homologous receptors.